The immune response to polysaccharide (PS) antigens is highly regulated and has several distinguishing features including restricted subclass, variable region gene usage, fine specificity, and avidity. Simple PS not conjugated to protein (such as bacterial levan (BL) or Neisseria meningitidis group C (MCPS)) elicit a thymus-independent (TI) response. PS conjugated to proteins (such as MCPS coupled to tetanus toxoid, (MCPS-TT)), on the other hand, elicit a different type of response, termed thymus-dependent (TD). Recent studies have shown that monoclonal antibodies (mAb) derived from mice immunized twice with a TI polysaccharide antigen, BL, can exhibit somatic mutations and affinity maturation, features previously thought to be properties only of responses to TD antigens. Among BL mAb, a single mutation encoding amino acid 53 in CDR2 correlated with increased antibody avidity. Ongoing studies involve site-directed mutagenesis and chain recombination to prove that this single site can alter the antibody avidity and to determine if it contributes to binding specificity. Dot blot and Northern analyses of anti-MCPS mAb reveal that VH gene family usage is dominated by VHJ558 (the largest VH gene family). These antibodies were not derived from a selected germ-line gene. The VHJ558 gene for 1705.18 resembles more closely the VHJ558 belonging to the anti-Dextran 19.1.2 group. 3006.18 and C2/974.1 resemble those anti-Dextran of group 9.14.7. The other mAb may represent a possible third group. Four of the mAb sequenced to date belong to the Vk4/5 family denoted VkOX1. This gene family is utilized in response to the hapten 2-phenyloxazolone. The sequences for the 1705.18, 1863.5 and 2055.5 mAbs are closely related. The 1922.2 mAb represents a different germ-line gene of the same family. Fine specificity and VH family usage do not seem to correlate with the exception of VH3609 mAbs which are specific for MCPS and are only found in response to the TI form. These antibodies are encoded by the VH3609.3 germline gene with very few changes. One Vk23 gene has been found to combine with VH3609 to bind MCPS. DNA sequence data indicated that several genes produced in response to MCPS are utilized also by auto-antibodies. Sequence analysis in progress will determine if somatic mutation can account for the increased diversity and increased avidity of the immune response to MCPS-TT over MCPS alone.